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Mechanisms of acidosis-mediated ischemic brain damage: Histopathology and pathophysiology

Li, Ping-An (1996)
Abstract
Exaggerated acidosis due to preischemic hyperglycemia shortens the maturation time for cell death and turns selective neuronal damage into pannecrosis. Some issues concerning the mechanisms are yet to be clarified. The present study was designed to define critical thresholds of plasma glucose, to investigate the influence of preischemic hyperglycemia on ion transients, to evaluate the role of calcium translocation in hyperglycemia-mediated damage, and to identify the targets of acidosis-mediated damage. The forebrain ischemic model of two-vessel occlusion plus hypotension was employed in male adult Wistar rats. Ca2+e, K+e, pHe, and DC potential were recorded continuously during pre- to postischemic periods. Histopathology was evaluated... (More)
Exaggerated acidosis due to preischemic hyperglycemia shortens the maturation time for cell death and turns selective neuronal damage into pannecrosis. Some issues concerning the mechanisms are yet to be clarified. The present study was designed to define critical thresholds of plasma glucose, to investigate the influence of preischemic hyperglycemia on ion transients, to evaluate the role of calcium translocation in hyperglycemia-mediated damage, and to identify the targets of acidosis-mediated damage. The forebrain ischemic model of two-vessel occlusion plus hypotension was employed in male adult Wistar rats. Ca2+e, K+e, pHe, and DC potential were recorded continuously during pre- to postischemic periods. Histopathology was evaluated after 7 days of recovery, bioenergetic states were analysed with fluorimetric enzymatic techniques, and microvascular patency was determined by a double staining technique. The results showed that hyperglycemia aggravates damage over a critical range of plasma glucose concentrations of 10 to 12 mM, corresponding to pHe values of 6.4 to 6.5. The mechanism of hyperglycemia-exaggerated damage can not be explained by further disturbance of Ca2+ metabolism since CA1 damage due 2.5 min of ischemia occurred in the absence of depolarization and Ca2+ influx. Furthermore, hyperglycemia shortens the periods of cell Ca2+ loading, compared to normo- or hypoglycemic animals. A subsequent bioenergetic study on animals subjected to 2.5 min of ischemia demonstrated a decreased ATP, an increased Pi, and increased lactate concentration. These changes, probably occurring in conjunc-tion with intracellular release of Ca2+ from sequestration sites, are postulated to trigger an MPT leading to mitochondrial failure and neuronal death. This notion was supported by the next study showing that pretreatment with the immunosuppressant CsA completely eliminated the CA1 damage. The present study also showed that it is likely the primary targets of acidosis-mediated damage are neurons rather than microvessels. Mitochondria appear to be an important subcellular target. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Hagberg, Henrik
publishing date
type
Thesis
publication status
published
subject
keywords
Neurology, Microvascular patency, Cyclosporin A, Bioenergetic state, Extracellular pH, Calcium transient, Neuronal damage, Hypoglycemia, Hyperglycemia, Cerebral ischemia, Acidosis, neuropsychology, neurophysiology, Neurologi, neuropsykologi, neurofysiologi
pages
87 pages
defense location
Segerfalksalen, Wallenber Neuroscience Center
defense date
1996-11-07 10:15
external identifiers
  • Other:LUMEDW (MEXB-1015-SE)
ISBN
91-628-2209-8
language
English
LU publication?
no
id
3e6f2cae-ddea-403e-a17f-398d6d4139dc (old id 17785)
date added to LUP
2007-05-24 10:32:00
date last changed
2016-09-19 08:45:16
@misc{3e6f2cae-ddea-403e-a17f-398d6d4139dc,
  abstract     = {Exaggerated acidosis due to preischemic hyperglycemia shortens the maturation time for cell death and turns selective neuronal damage into pannecrosis. Some issues concerning the mechanisms are yet to be clarified. The present study was designed to define critical thresholds of plasma glucose, to investigate the influence of preischemic hyperglycemia on ion transients, to evaluate the role of calcium translocation in hyperglycemia-mediated damage, and to identify the targets of acidosis-mediated damage. The forebrain ischemic model of two-vessel occlusion plus hypotension was employed in male adult Wistar rats. Ca2+e, K+e, pHe, and DC potential were recorded continuously during pre- to postischemic periods. Histopathology was evaluated after 7 days of recovery, bioenergetic states were analysed with fluorimetric enzymatic techniques, and microvascular patency was determined by a double staining technique. The results showed that hyperglycemia aggravates damage over a critical range of plasma glucose concentrations of 10 to 12 mM, corresponding to pHe values of 6.4 to 6.5. The mechanism of hyperglycemia-exaggerated damage can not be explained by further disturbance of Ca2+ metabolism since CA1 damage due 2.5 min of ischemia occurred in the absence of depolarization and Ca2+ influx. Furthermore, hyperglycemia shortens the periods of cell Ca2+ loading, compared to normo- or hypoglycemic animals. A subsequent bioenergetic study on animals subjected to 2.5 min of ischemia demonstrated a decreased ATP, an increased Pi, and increased lactate concentration. These changes, probably occurring in conjunc-tion with intracellular release of Ca2+ from sequestration sites, are postulated to trigger an MPT leading to mitochondrial failure and neuronal death. This notion was supported by the next study showing that pretreatment with the immunosuppressant CsA completely eliminated the CA1 damage. The present study also showed that it is likely the primary targets of acidosis-mediated damage are neurons rather than microvessels. Mitochondria appear to be an important subcellular target.},
  author       = {Li, Ping-An},
  isbn         = {91-628-2209-8},
  keyword      = {Neurology,Microvascular patency,Cyclosporin A,Bioenergetic state,Extracellular pH,Calcium transient,Neuronal damage,Hypoglycemia,Hyperglycemia,Cerebral ischemia,Acidosis,neuropsychology,neurophysiology,Neurologi,neuropsykologi,neurofysiologi},
  language     = {eng},
  pages        = {87},
  title        = {Mechanisms of acidosis-mediated ischemic brain damage: Histopathology and pathophysiology},
  year         = {1996},
}